density functional theory calculations have been performed to elucidate the new reaction mechanism of oxidative cleavage of Trp; density functional theory calculations have been performed to elucidate the reaction mechanism of oxidative cleavage of Trp

electrophilic or radical addition reaction mechanism via formation of a transient ferryl intermediate, assigned as a Compound II (ferryl) species, during oxidation of L-Trp, 1-methyl-L-Trp, and a number of other substrate analogues, overview. A common reaction mechanism for indoleamine 2,3-dioxygenase-catalyzed oxidation of tryptophan and other tryptophan analogues is determined

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SYSTEMATIC NAME

IUBMB Comments

D-tryptophan:oxygen 2,3-oxidoreductase (decyclizing)

A protohemoprotein. Requires ascorbic acid and methylene blue for activity. This enzyme has broader substrate specificity than EC 1.13.11.11, tryptophan 2,3-dioxygenase [1]. It is induced in response to pathological conditions and host-defense mechanisms and its distribution in mammals is not confined to the liver [2]. While the enzyme is more active with D-tryptophan than L-tryptophan, its only known function to date is in the metabolism of L-tryptophan [2,6]. Superoxide radicals can replace O2 as oxygen donor [4,7].

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species; indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) enzymes have independently evolved to catalyze the first step in the catabolism of tryptophan (L-Trp) through the kynurenine pathway. Enzyme TDO is found in almost all metazoan and many bacterial species, but not in fungi, distribution of IDO/TDO genes among invertebrates, overview. Some lineages have independently generated multiple IDO paralogues through gene duplications. Only mammalian IDO1s and fungal typical IDOs have high affinity and catalytic efficiency for L-Trp catabolism, comparable to TDOs. Invertebrate IDO enzymes have low affinity and catalytic efficiency for L-Trp catabolism. Phylogenetic analysis. the phylogenetic distribution of low catalytic-efficiency IDOs indicates the ancestral IDO also had low affinity and catalytic efficiency for L-Trp catabolism. IDOs with high catalytic-efficiency for L-Trp catabolism may have evolved in certain lineages to fulfill particular biological roles. The low catalytic efficiency IDOs have been well conserved in a number of lineages throughout their evolution, although it is not clear that the enzymes contribute significantly to L-Trp catabolism in these species

IDO inhibition significantly affects the ability of CD103+ denxritic cells to promote conversion of naive T cells into Foxp3+Tregs while the ability of CD103- cells is unaffected. IDO inhibition impinges on the development of oral tolerance

IDO inhibition significantly affects the ability of CD103+ dendritic cells to promote conversion of naive T cells into Foxp3+Tregs while the ability of CD103- cells is unaffected. IDO inhibition impinges on the development of oral tolerance

IDO1 pharmacological inhibition causes the rejection of mouse allogeneic concepti, mediated by T cells, and its expression in tumors is associated with their immune evasion. Deletion of IDO1 genomic sequences has the potential to also impact on IDO2 expression due to the chromosomal proximity of the genes, transcription of the IDO2 gene is reduced in the liver of IDO1-/- mice, although protein levels appear to be maintained

three enzymes are now known to catalyze the first and rate-limiting step in the catabolism of tryptophan along the kynurenine pathway: tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase subsequently and a third enzyme, indoleamine 2,3-dioxygenase 2. The kynurenine pathway is a major route for NAD+ synthesis. The pathway is implicated in many disorders and/or their complications, including cerebral malaria, neurological and neurodegenerative diseases

three enzymes are now known to catalyze the first and rate-limiting step in the catabolism of tryptophan along the kynurenine pathway: tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase subsequently and a third enzyme, indoleamine 2,3-dioxygenase 2. The kynurenine pathway is a major route for NAD+ synthesis. The pathway is implicated in many disorders and/or their complications, including cerebral malaria, neurological and neurodegenerative diseases

indoleamine 2,3-dioxygenase catalyzes the first step in tryptophan breakdown along the kynurenine pathway; indoleamine 2,3-dioxygenase catalyzes the first step in tryptophan breakdown along the kynurenine pathway

indoleamine 2,3-dioxygenase-2 (IDO2) is one of three enzymes, alongside tryptophan 2,3-dioxygenase (EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO1), that catalyse dioxygenation of L-tryptophan as the first step in the kynurenine pathway; indoleamine 2,3-dioxygenase-2 (IDO2) is one of three enzymes, alongside tryptophan 2,3-dioxygenase (EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO1), that catalyse dioxygenation of L-tryptophan as the first step in the kynurenine pathway

comparison of contribution percentage of tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO) to the conversion of L-tryptophan, the calculated percentage conversions indicats that TDO and IDO oxidize 70% and 30%, respectively, of the dietary L-tryptophan. The amount of D-Trp converted to nicotinamide via indole-3-pyruvic acid (IPA) is very low, this amount of D-Trp is converted to L-Trp, which is primarily used for protein synthesis rather than catabolism via the Kyn biosynthesis pathway in mice

the initial and rate-limiting step of the kynurenine pathway involves oxidation of L-Trp toN-formylkynurenine. This is an O2-dependent process and catalyzed by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, EC 1.13.11.11

the first and rate limiting step of the kynurenine pathway is carried out by two heme-containing enzymes, tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO), which differ in their tissue distribution and regulation

comparison of contribution percentage of tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO) to the conversion of L-tryptophan, the calculated percentage conversions indicats that TDO and IDO oxidize 70% and 30%, respectively, of the dietary L-tryptophan. The amount of D-Trp converted to nicotinamide via indole-3-pyruvic acid (IPA) is very low, this amount of D-Trp is converted to L-Trp, which is primarily used for protein synthesis rather than catabolism via the Kyn biosynthesis pathway in mice

indoleamine 2,3-dioxygenase activity is implicated in the promotion of tolerance to tumors and in autoimmune and inflammatory conditions, itplays a role in arthritis, ischemia-reperfusion injury, haemostatic system, sepsis, atherosclerosis, diabetes, and gut, allergy, and airway inflammation

the induction of IDO by interferon-gamma in HLE-B3 cells causes increases in intracellular reactive oxygen species, cytosolic cytochrome c and caspase-3 activity, along with a decrease in protein-free thiol content, are accompanied by apoptosis. IDO-mediated kynurenine formation plays a role in cataract formation related to chronic inflammation

activation of IDO is a key event in the switch from sickness to depression, activation of the innate immune system in the brain is sufficient to activate IDO and to induce depressive-like behavior in the absence of detectable interferon-gamma

TDO expression distinguishes stem cells from more differentiated cells among the granule cells of the adult mouse dentate gyrus. TDO is required at a late-stage of granule cell development, such as during axonal and dendritic growth, synaptogenesis and its maturation

in mammals, IDO1 acts as a defence molecule in combating bacterial and viral infections, as its expression is up-regulated by cytokines such as IFN-gamma, leading to local depletion of L-Trp and causing inhibition of pathogen growth

in mammals, IDO1 acts as a defence molecule in combating bacterial and viral infections, as its expression is up-regulated by cytokines such as IFN-gamma, leading to local depletion of L-Trp and causing inhibition of pathogen growth. IDO2 mRNA is also upregulated in the brain of mice infected with Toxoplasma gondii, an infection in which IFN-gamma driven responses play an important role in controlling parasite growth

heme enzyme indoleamine 2,3-dioxygenase is a key regulator of immune responses through catalyzing L-tryptophan oxidation. Peroxidase-mediated dioxygenase inactivation, NO consumption, or protein nitration may modulate the biological actions of IDO expressed in inflammatory tissues where the levels of H2O2 and NO are elevated and L-Trp is low

immune regulatory effects of Ido1 and ability of nitric oxide to regulate Ido1 activity, Ido1-mediated metabolism of tryptophan to kynurenine can modulate vascular tone After transient cerebral ischaemia induction in wild-type and Ido1 gene-deficient (Ido1-/-) mice, cerebral ischaemia-reperfusion in wild-type mice increases Ido activity and its expression in cerebral arterioles, while Ido1-/- and 1-methyl-D-tryptophan-treated wild-type mice have lower Ido activity but similar post-stroke neurological function and similar total brain infarct volume and swelling, relative to control mice. Ido1 expression does not appear to affect overall outcome following acute ischaemic stroke

the enzyme is involved in nicotinamide biosynthesis. Comparison of contribution percentage of tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO) to the conversion of L-tryptophan, the calculated percentage conversions indicats that TDO and IDO oxidize 70% and 30%, respectively, of the dietary L-tryptophan. The amount of D-Trp converted to nicotinamide via indole-3-pyruvic acid (IPA) is very low, this amount of D-Trp is converted to L-Trp, which is primarily used for protein synthesis rather than catabolism via the Kyn biosynthesis pathway in mice

the enzyme catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumors, autoimmune diseases, and different kinds of inflammation

the enzyme catalyses the first and rate-limiting step in the metabolism of L-tryptophan. Degradation of L-Trp leads to the production of several immunosuppressive metabolites, including N-formyl kynurenine and kynurenine. Enzyme IDO-1 also plays a crucial role in immune suppression and tumour induced tolerance. IDO-1 acts as an inducible negative regulator of T cell viability, proliferation and activation

the enzyme is involved in nicotinamide biosynthesis. Comparison of contribution percentage of tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO) to the conversion of L-tryptophan, the calculated percentage conversions indicats that TDO and IDO oxidize 70% and 30%, respectively, of the dietary L-tryptophan. The amount of D-Trp converted to nicotinamide via indole-3-pyruvic acid (IPA) is very low, this amount of D-Trp is converted to L-Trp, which is primarily used for protein synthesis rather than catabolism via the Kyn biosynthesis pathway in mice

Xanthomonas campestris TDO shows an H-bond between T254 and the ammonium group of the substrate is present in the L-Trp-bound enzyme, but not in the D-Trp bound enzyme, molecular dynamics simulation studies. T254 controls the substrate stereoselectivity of the enzyme by modulating the H-bonding interaction between the NH3-group and epoxide oxygen of the ferryl/indole 2,3-epoxide intermediate of the enzyme, and regulating the dynamics of two active site loops, loop250-260 and loop117-130, critical for substrate-binding, O2 and L-trp both are bound in the active site

human indoleamine 2,3-dioxygenase-2 substrate specificity and inhibition characteristics are distinct from those of indoleamine 2,3-dioxygenase-1; human indoleamine 2,3-dioxygenase-2 substrate specificity and inhibition characteristics are distinct from those of indoleamine 2,3-dioxygenase-1

important amino acid residues that stabilize the substrate in the active site: a cluster of small side chain residues at positions 260-265 ensures structural flexibility of the binding site. Thr379 and Arg231 are key residues acting in concert to bind the substrate. Thr379 is the final residue of a disordered loop, the neighboring Gly380 is 20 A away from the heme iron. Residues Ser167, Phe226, Phe227, and Arg231 may play critical roles. Stucture-function analysis by spectrocopic methods, overview. The hIDO1 distal heme pocket is in part lined by a sequence of residues with small side chains (residues 260-265: AGGSAG) rendering structural flexibility to the active site, which may be required to accommodate the substrate

altered kinetics for IPA (very long lag phase) as being consistent with a role for the ammonium group in stabilizing the ferric superoxide complex (via the radical pathway). The rate-limiting steps are different from the other substrates examined so that Compound II does not accumulate, but product formation is still possible, product formation ananlysis by LC-MS

if the cellular environment protects indoleamine 2,3-dioxygenase from oxidation to the ferric form, no additional electron donor might by required for indolamine 2,3-dioxygenase activity in intact tissues

the initial deprotonation reaction of the indole NH group in hTDO is carried out by the evolutionarily conserved distal His. stereospecificity of hTDO is determined by the efficiency of the dioxygen chemistry

during larval life the enzyme controls the level of potentially harmful free Trp in the hemolymph by converting it to kynurenine, and during adult development the enzyme catalyzes the first step of brown eye pigment biosynthesis

proposed reaction mechanism involves the proton abstraction by iron-bound dixoygen. The O-O bond is precisely controlled by the heme proximal and distal environment and is not cleaved before the incorporation of both oxygen atoms into the substrate

a dramatic and specific induction of the pulmonary enzyme by virus and lipopolysaccharide is mediated by interferon. The enzyme may play an important role in the inflammatory processes, immune responses, and/or the mode of action of interferon

enzyme shows induced-fit mechanism to bind L-Trp, two conserved but flexible loops undergo conformational changes, converting the active site from an open conformation to a closed conformation, key residues involved in recognition and binding of the heme and the substrate, Molecular modeling and dynamics simulation, overview

the initial deprotonation reaction of the indole NH group in hTDO is carried out by the evolutionarily conserved distal His. stereospecificity of hTDO is determined by the efficiency of the dioxygen chemistry

the enzyme has broad substrate specificity for various indoleamines such as L-tryptophan and serotonin. It catalyzes the oxidation of the pyrrole ring of tryptophan to form N-formylkynurenine, which is later metabolized to formic acid and kynurenine

indoleamine 2,3-dioxygenase is a rate-limiting enzyme in the L-tryptophan-kynurenine pathway. IFN-gamma-induced expression of IDO expression is inhibited only by JAK inhibitor I. Lipopolysaccharide-induced expression of indoleamine 2,3-dioxygenase is inhibited by LY294002 and SP600125 but not by JAK inhibitor I, SB203580, or U0126. LPS can induce the expression of indoleamine 2,3-dioxygenase via an IFN-gamma-independent mechanism and PI3 kinase and JNK in the LPS-induced pathway leading to IDO expression

the enzyme has broad substrate specificity for various indoleamines such as L-tryptophan and serotonin. It catalyzes the oxidation of the pyrrole ring of tryptophan to form N-formylkynurenine, which is later metabolized to formic acid and kynurenine

in the placenta, inhibition of the enzyme leads to spontaneous abortion. By catabolizing extracellular tryptophan the enzyme inhibits local T cell proliferation thereby preventing placental rejection. This mechanism can also be active in suppressing inflammatory responses in the central neurvous system, where inflammation must be tightly regulated to prevent the loss of irreplaceable neurons. Local expression of the enzyme during inflammation is a self-protection mechanism which limits antigen-specific immune responses in the central nervous system

the enzyme plays an important physiological role in the defense mechanism against a variety of infectious pathogens, in the regulation of T-cell function by macrophages and a subset of dendritic cells, and in the synthesis of UV filters in human lenses. Serious problems arise from the unregulated over-expression of the enzyme, which often results in a deleterious systemic Trp depletion and/or the accumulation of neurotoxin, quinolinic acidn the brain. Enzyme expression in malignant tumors helps them to avoid the immune surveillance through a local Trp depletion. The kynurenilation of the lens protein with UV filters thus appears to be the major cause of age-related cataract

docking calculations and spatial coarse graining simulations are used to determine the molecular basis of substrate recognition, enhancer binding and conformational transitions of IDO in response to these events

the enzyme catalyzes the oxidation of indole by H2O2, with generation of 2- and 3-oxoindole as the major products, in the absence of O2 and reducing agents and is not inhibited by superoxide dismutase or hydroxyl radical scavengers, although it is strongly inhibited by L-Trp. IDO inserts oxygen into indole in a reaction that is mechanistically analogous to the peroxide shunt pathway of cytochrome P450

substrate specificity, overview. Replacement of the 5-methoxy group by a methyl group has a negative influence in the binding of the molecule, decreasing its affinity threefold. 5-HO-L-Trp and melatonin are no substrates for IDO2

using a cytochrome b5-based activating system, the initial rates of O2 decay with a Clark-type oxygen electrode at physiologically-relevant levels of both substrates are measured. Kinetics are also studied in the presence of two inhibitory substrate analogues: 1-methyl L-tryptophan and norharmane. Quantitative analysis supports a steady-state rather than a rapid equilibrium kinetic mechanism, where the rates of individual pathways, leading to a ternary complex, are significantly different, and the overall rate of catalysis depends on contributions of both routes. One path, where O2 binds to ferrous hIDO1 first, is faster than the second route, which starts with the binding of L-Trp. L-Trp complexation with free ferrous hIDO1 is more rapid than that of O2. As the level of L-Trp increases, the slower route becomes a significant contributor to the overall rate, resulting in observed substrate inhibition. When 1-Me-L-Trp is the only indoleamine in the reaction mixture, it is a very slow substrate for hIDO1

during larval life the enzyme controls the level of potentially harmful free Trp in the hemolymph by converting it to kynurenine, and during adult development the enzyme catalyzes the first step of brown eye pigment biosynthesis

a dramatic and specific induction of the pulmonary enzyme by virus and lipopolysaccharide is mediated by interferon. The enzyme may play an important role in the inflammatory processes, immune responses, and/or the mode of action of interferon

indoleamine 2,3-dioxygenase is a rate-limiting enzyme in the L-tryptophan-kynurenine pathway. IFN-gamma-induced expression of IDO expression is inhibited only by JAK inhibitor I. Lipopolysaccharide-induced expression of indoleamine 2,3-dioxygenase is inhibited by LY294002 and SP600125 but not by JAK inhibitor I, SB203580, or U0126. LPS can induce the expression of indoleamine 2,3-dioxygenase via an IFN-gamma-independent mechanism and PI3 kinase and JNK in the LPS-induced pathway leading to IDO expression

in the placenta, inhibition of the enzyme leads to spontaneous abortion. By catabolizing extracellular tryptophan the enzyme inhibits local T cell proliferation thereby preventing placental rejection. This mechanism can also be active in suppressing inflammatory responses in the central neurvous system, where inflammation must be tightly regulated to prevent the loss of irreplaceable neurons. Local expression of the enzyme during inflammation is a self-protection mechanism which limits antigen-specific immune responses in the central nervous system

the enzyme plays an important physiological role in the defense mechanism against a variety of infectious pathogens, in the regulation of T-cell function by macrophages and a subset of dendritic cells, and in the synthesis of UV filters in human lenses. Serious problems arise from the unregulated over-expression of the enzyme, which often results in a deleterious systemic Trp depletion and/or the accumulation of neurotoxin, quinolinic acidn the brain. Enzyme expression in malignant tumors helps them to avoid the immune surveillance through a local Trp depletion. The kynurenilation of the lens protein with UV filters thus appears to be the major cause of age-related cataract

the enzyme catalyzes the oxidation of indole by H2O2, with generation of 2- and 3-oxoindole as the major products, in the absence of O2 and reducing agents and is not inhibited by superoxide dismutase or hydroxyl radical scavengers, although it is strongly inhibited by L-Trp. IDO inserts oxygen into indole in a reaction that is mechanistically analogous to the peroxide shunt pathway of cytochrome P450

characterization of the heme environment, strong proximal Fe-His bond and strond H-bonding and/or steric interactions between L-Trp and dioxygen in the distal pocket are likely crucial for the enzymatic activity of the recombinant enzyme

hemoprotein. The use of ALA, the biosynthetic precursor of protoporphyrin IX, coupled with metal-affinity chromatography and size exclusion chromatography produces 6His-IDP with a protein to heme ratio of 1:2.2

none of the polar amino acid residues in the distal heme pocket are essential for activity. The O-O bond is precisely controlled by the heme proximal and distal environment and is not cleaved before the incorporation of both oxygen atoms into the substrate

the active-site heme is essential for IDO dioxygenase activity, reduction of heme from the ferric (FeIII) to the ferrous (FeII) form facilitates binding of O2 and L-Trp to form the active ternary complex